The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder

Glahn, David C.; Bearden, Carrie E.; Niendam, Tara A.; Escamilla, Michael

doi:10.1111/j.1399-5618.2004.00113.x

Cited by 238 publications

(166 citation statements)

References 127 publications

(137 reference statements)

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“…Glahn et al 153 have elegantly reviewed the evidence supporting the use of cognitive endophenotypes in BD; the data supporting this approach are therefore only briefly summarized below. A number of cognitive domains appear to be highly heritable; as well as the known heritability of general intelligence, performance on tests assessing information processing, attention, working and declarative memory as well as executive function is strongly genetically influenced.…”

Section: Cognitive Endophenotypesmentioning

confidence: 99%

The phenotypes of bipolar disorder: relevance for genetic investigations

2005

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The search for susceptibility genes for bipolar disorder (BD) depends on appropriate definitions of the phenotype. In this paper, we review data on diagnosis and clinical features of BD that could be used in genetic studies to better characterize patients or to define homogeneous subgroups. Clinical symptoms, long-term course, comorbid conditions, and response to prophylactic treatment may define groups associated with more or less specific loci. One such group is characterized by symptoms of psychosis and linkage to 13q and 22q. A second group includes mainly bipolar II patients with comorbid panic disorder, rapid mood switching, and evidence of chromosome 18 linkage. A third group comprises typical BD with an episodic course and favourable response to lithium prophylaxis. Reproducibility of cognitive deficits across studies raises the possibility of using cognitive profiles as endophenotypes of BD, with deficits in verbal explicit memory and executive function commonly reported. Brain imaging provides a more ambiguous data set consistent with heterogeneity of the illness. Keywords: bipolar disorder; genetics; endophenotype; neurocognitive function; brain imaging Bipolar disorder (BD) has a genetic basis with heritability of at least 80%. 1 A number of studies have attempted to map the susceptibility loci giving evidence of linkage in multiple genomic regions. In particular, findings in 4p, 4q, 8q, 10p, 12q24, 13q, 18p, 18q, 21q, and 22q have been supported by more than one study. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] However, these studies have not identified any specific genes, and a recent metaanalysis of available genome scans showed no regions with a conclusive evidence of linkage. 20 The relatively slow progress of gene-mapping efforts is often explained by the 'complex' nature of the illness and of the genotype-phenotype relation. The complexity most likely includes heterogeneity, interactions of multiple loci, incomplete penetrance, as well as phenotypes resulting from environmental effects-either alone or in interaction with the genetic predisposition. The goal of psychiatric genetic research is identification of (heritable) variations in DNA sequence or function that influence behaviour or give rise to mental illness. By definition, in complex (multifactorial) traits, this link is not unique and specific. That is, a particular change in gene sequence does not necessarily lead to a specific behaviour, and similar behaviours (symptoms) may be due to distinct (sets of) genes. Moreover, we must consider the possibility that the path between the genotype and behaviour is not unidirectional. Emerging examples point not only to general effects of environment, for instance stress, on behaviour, but also to specific behaviours influencing gene function that can be transmitted onto the next generation. 21 No single method is considered clearly superior in identifying susceptibility genes for complex traits such as BD. Most researchers agree that a combination of strategies is most lik...

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Section: Cognitive Endophenotypesmentioning

confidence: 99%

The phenotypes of bipolar disorder: relevance for genetic investigations

2005

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“…Recently published meta-analyses have shown that executive functions and verbal memory are the most impaired cognitive domains in euthymic patients (Robinson et al 2006 ;Torres et al 2007) as well as attention/ processing speed (Torres et al 2007). These neurocognitive deficits have been postulated to constitute trait markers or endophenotypes of BD (Glahn et al 2004 ;Savitz et al 2005), but the specific neurocognitive and therefore endophenotypic status of BD II and other bipolar spectrum disorders remains unclear (Savitz et al 2008). Moreover, the concept of allostatic load is interesting in order to explain cognitive impairment in BD.…”

Section: Introductionmentioning

confidence: 99%

Are bipolar II patients cognitively impaired? A systematic review

et al. 2011

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Background. There is evidence that bipolar disorder (BD) is associated with significant neurocognitive deficits and this occurs in individuals with BD type I (BD I) and with BD type II (BD II). Only a few studies have focused on cognitive impairment in BD II. The aim of this study was to describe the pattern of cognitive impairment in patients with BD II, in order to identify specific cognitive deficits that distinguish BD II from BD I patients as well as from healthy subjects.Method. We performed a systematic review of the literature of neuropsychological studies of BD II published between 1980 and July 2009. Fourteen articles fulfilled the inclusion criteria and were included in this review.Results. Main cognitive deficits found in BD II include working memory and some measures of executive functions (inhibitory control) and approximately half of the studies also detected verbal memory impairment.Conclusions. There are subtle differences between the two subtypes regarding cognition. This may suggest neurobiological differences between the two subgroups which will be helpful in order to determine cognitive endophenotypes in BD subtypes.

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“…1,44 However, relatively little is known about the genetics of these dysfunctions, although their potential in the search for genetic associations has been recognized. 34,69,108 There is substantial evidence that schizophrenia is likely to be a complex genetic disorder, with multiple risk genes of individually weak effect. 79 Therefore, a multivariate approach, capable of extracting hidden cross-information from a larger number of genes, has the potential to uncover influences of multiple genetic factors on the functions of both healthy and disordered brains.…”

Section: Introductionmentioning

confidence: 99%

Physiogenomic Analysis of Localized fMRI Brain Activity in Schizophrenia

et al. 2008

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The search for genetic factors associated with disease is complicated by the complexity of the biological pathways linking genotype and phenotype. This analytical complexity is particularly concerning in diseases historically lacking reliable diagnostic biological markers, such as schizophrenia and other mental disorders. We investigate the use of functional magnetic resonance imaging (fMRI) as an intermediate phenotype (endophenotype) to identify physiogenomic associations to schizophrenia. We screened 99 subjects, 30 subjects diagnosed with schizophrenia, 13 unaffected relatives of schizophrenia patients, and 56 unrelated controls, for gene polymorphisms associated with fMRI activation patterns at two locations in temporal and frontal lobes previously implied in schizophrenia. A total of 22 single nucleotide polymorphisms (SNPs) in 15 genes from the dopamine and serotonin neurotransmission pathways were genotyped in all subjects. We identified three SNPs in genes that are significantly associated with fMRI activity. SNPs of the dopamine beta-hydroxylase (DBH) gene and of the dopamine receptor D4 (DRD4) were associated with activity in the temporal and frontal lobes, respectively. One SNP of serotonin-3A receptor (HTR3A) was associated with temporal lobe activity. The results of this study support the physiogenomic analysis of neuroimaging data to discover associations between genotype and disease-related phenotypes.

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The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder

Abstract: Molecular genetic studies of BPD may benefit from the application of select neuropsychological measures as endophenotypic markers. The use of these markers, once defined, may improve power for detecting genes predisposing to BPD and may help to better define diagnostic criteria.

Cited by 238 publications

References 127 publications

The phenotypes of bipolar disorder: relevance for genetic investigations

The phenotypes of bipolar disorder: relevance for genetic investigations

Are bipolar II patients cognitively impaired? A systematic review

Physiogenomic Analysis of Localized fMRI Brain Activity in Schizophrenia

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